Enterolactone but not genistein decreases estradiol-induced tumor growth, angiogenesis, and secreted VEGF in vivo in human breast cancer.

Abstract

Abstract Abstract #5081 Phytoestrogens have been shown to be potential compounds in breast cancer prevention and treatment by poorly understood mechanisms. There are two major classes of phytoestrogens in the diet; lignans and isoflavones. One main phytoestrogen in Western diet is the mammalian lignan enterolactone (ENL) whereas soy is the major source of the isoflavone genistein (GEN) usually found in Eastern diets. In this paper we investigated the effects of ENL and GEN on estradiol induced breast cancer growth in nude mice. Ovariectomized mice treated with a continuous release of estradiol were used. MCF-7 tumors were established and mice were fed with basal diet (BD), or BD with added ENL, GEN, or a combination of ENL and GEN. Tumor growth was followed and microdialysis was used to sample extracellular VEGF and FGF-2 in vivo after 2-3 weeks of treatment. We show that ENL alone or in combination with GEN, counteracted estradiol-induced growth and angiogenesis of solid tumors. GEN alone did not affect tumor growth or angiogenesis compared with BD. The pro-angiogenic extracellular levels of VEGF in vivo were significantly decreased by ENL and ENL+GEN diets compared with tumors in the BD group whereas GEN diet alone did not affect the levels compared with BD. FGF-2 levels were similar in all groups. Our in vivo findings were confirmed in vitro. By adding ENL and/or GEN, estradiol-induced VEGF secretion in MCF-7 cells decreased significantly in the ENL and ENL+GEN groups whereas GEN alone had no effects compared with estradiol exposed cells. FGF-2 was unaffected by estrogen and phytoestrogen exposure compared with control cells without added hormones. Estradiol up-regulated VEGFR-2 in human umbilical vein endothelial cells and this up-regulation was inhibited by ENL suggesting a pro-angiogenic effect by estradiol by two different mechanisms, both of which were inhibited by the addition of ENL. Our results suggest that ENL has potent anti-estrogenic effects on ER+ breast cancer whereas GEN failed to inhibit estradiol-induced tumor growth and VEGF secretion. Various phytoestrogens may have very different effects on breast cancer. ENL may prove to be beneficial in breast cancer prevention strategies in the future while GEN may cause opposite effects. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5081.